Article

TM4SF20 Ancestral Deletion and Susceptibility to a Pediatric Disorder of Early Language Delay and Cerebral White Matter Hyperintensities

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 06/2013; 93(2). DOI: 10.1016/j.ajhg.2013.05.027
Source: PubMed

ABSTRACT White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ∼70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.

Download full-text

Full-text

Available from: Sau Wai Cheung, Mar 26, 2014
1 Follower
 · 
223 Views
  • Source
    • "Non-European populations carry a number of unique genetic variants not found in Europeans, some of which might contribute to risk of language-related problems. A recent example is the report of a deletion in TM4SF20 in southeast Asian populations implicated in language delay and cerebral white matter hyperintensities, probably via production of a toxic protein (OMIM 615432) (Wiszniewski et al. 2013). Second, languages are diverse in their phonology and syntax (Evans and Levinson 2009), and also in their orthographic systems, which leads to different manifestations of disorders such as SLI and dyslexia (Leonard 2014; Richlan 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior.
    Neuropsychology Review 01/2015; 25(1). DOI:10.1007/s11065-014-9277-2 · 5.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Homozygosity for a recurrent 290 kb deletion of NPHP1 is the most frequent cause of isolated nephronophthisis (NPHP) in humans. A deletion of the same genomic interval has also been detected in individuals with Joubert syndrome (JBTS), and in the mouse, Nphp1 interacts genetically with Ahi1, a known JBTS locus. Given these observations, we investigated the contribution of NPHP1 in Bardet-Biedl syndrome (BBS), a ciliopathy of intermediate severity. By using a combination of array-comparative genomic hybridization, TaqMan copy number assays, and sequencing, we studied 200 families affected by BBS. We report a homozygous NPHP1 deletion CNV in a family with classical BBS that is transmitted with autosomal-recessive inheritance. Further, we identified heterozygous NPHP1 deletions in two more unrelated persons with BBS who bear primary mutations at another BBS locus. In parallel, we identified five families harboring an SNV in NPHP1 resulting in a conserved missense change, c.14G>T (p.Arg5Leu), that is enriched in our Hispanic pedigrees; in each case, affected individuals carried additional bona fide pathogenic alleles in another BBS gene. In vivo functional modeling in zebrafish embryos demonstrated that c.14G>T is a loss-of-function variant, and suppression of nphp1 in concert with each of the primary BBS loci found in our NPHP1-positive pedigrees exacerbated the severity of the phenotype. These results suggest that NPHP1 mutations are probably rare primary causes of BBS that contribute to the mutational burden of the disorder.
    The American Journal of Human Genetics 04/2014; 94(5). DOI:10.1016/j.ajhg.2014.03.017 · 10.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and not identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunologic evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, presence of CD8+ T cells, poor lymphocyte proliferation, hypergammaglobulinemia, and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in pre-transplant blood and buccal DNA, and maternal engraftment (5-10%) demonstrated in pre-transplant blood DNA. This may be responsible for the patient's unusual immunologic phenotype compared to classical IL7Ralpha deficiency. Disseminated VZV was controlled with antiviral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T-cell receptor excision circles (TREC) analyses completed on neonatal Guthrie cards from the patient identified absent TRECs. This case emphasizes the danger of live viral vaccination in SCID patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality, and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic etiology for SCID patients.
    Clinical & Experimental Immunology 07/2014; 178(3). DOI:10.1111/cei.12421 · 3.28 Impact Factor
Show more